Aminopyrimidine derivatives for use as modulators of kinase activity

ABSTRACT

The invention provides novel heterocyclic amine compounds according to Formula (I) and their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

RELATED APPLICATIONS

This application is a CONTINUATION application of U.S. Ser. No.15/060,050, filed on Mar. 3, 2016, which is a DIVISIONAL application ofU.S. Ser. No. 14/236,405, which is a U.S. national stage application ofPCT international application PCT/US2012/054877, filed on Sep. 12, 2012,which claims the benefit of U.S. provisional application U.S. Ser. No.61/533,606, filed on Sep. 12, 2011. The entire contents of theaforementioned applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention relates to a series of heterocyclic amine compounds thatare useful in the treatment of hyperproliferative diseases, such ascancer, in mammals. Also encompassed by the present invention is the useof such compounds in the treatment of hyperproliferative diseases inmammals, especially humans, and pharmaceutical compositions containingsuch compounds.

SUMMARY OF THE RELATED ART

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Protein kinase 70S6K, the 70 kDa ribosomal protein kinase p70S6K (alsoknown as SK6, p70/p85 S6 kinase, p70/p85 ribosomal S6 kinase andpp70S6K), is a member of the AGC subfamily of protein kinases. p70S6K isa serine-threonine kinase that is a component of thephosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is downstreamof PI3K, and activation occurs through phosphorylation at a number ofsites in response to numerous mitogens, hormones and growth factors.p70S6K activity is also under the control of a mTOR-containing complex(TORC1) since rapamycin acts to inhibit p70S6K activity. p70S6K isregulated by PI3K downstream targets AKT and PKCζ. Akt directlyphosphorylates and inactivates TSC2, thereby activating mTOR. Inaddition, studies with mutant alleles of p70S6K that inhibited byWortmannin but not by rapamycin suggest that the PI3K pathway canexhibit effects on p70S6K independent of the regulation of mTORactivity.

The enzyme p70S6K modulates protein synthesis by phosphorylation of theS6 ribosomal protein. S6 phosphorylation correlates with increasedtranslation of mRNAs encoding components of the translational apparatus,including ribosomal proteins and translational elongation factors whoseincreased expression is essential for cell growth and proliferation.These mRNAs contain an oligopyrimidime tract at their 5′ transcriptionalstart (termed 5′TOP), which has been shown to be essential for theirregulation at the translational level.

In addition to its involvement in translation, p70S6K activation hasalso been implicated in cell cycle control, neuronal celldifferentiation, regulation of cell motility and a cellular responsethat is important in tumor metastases, the immune response and tissuerepair. Antibodies to p70S6K abolish the mitogenic response driven entryof rat fibroblasts into S phase, indication that p70S6K function isessential for the progression from G1 to S phase in the cell cycle.Furthermore, inhibition of cell cycle proliferation at the G1 to S phaseof the cell cycle by rapamycin has been identified as a consequence ofinhibition of the production of the hyperphosphorylated, activated formof p70S6K.

A role for p70S6K in tumor cell proliferation and protection of cellsfrom apoptosis is supported based on it participation in growth factorreceptor signal transduction, overexpression and activation in tumortissues. For example, Northern and Western analyses revealed thatamplification of the PS6K gene was accompanied by correspondingincreases in mRNA and protein expression, respectively (Cancer Res.(1999) 59: 1408-11-Localization of PS6K to Chromosomal Region 17q23 andDetermination of Its Amplification in Breast Cancer).

Chromosome 17q23 is amplified in up to 20% of primary breast tumors, in87% of breast tumors containing BRCA2 mutations and in 50% of tumorscontaining BRCA1 mutations, as well as other cancer types such aspancreatic, bladder and neuroblastoma (see M. Barlund, O. Monni, J.Kononen, R. Cornelison, J. Torhorst, G. Sauter, O.-P. Kallioniemi andKallioniemi A., Cancer Res., 2000, 60:5340-5346). It has been shown that17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K,and SIGMA1B genes (Cancer Res. (2000): 60, pp. 5371-5375).

The p70S6K gene has been identified as a target of amplification andoverexpression in this region, and statistically significant associationbetween amplification and poor prognosis has been observed. Clinicalinhibition of p70S6K activation was observed in renal carcinoma patientstreated with CCI-779 (rapamycin ester), an inhibitor of the upstreamkinase mTOR. A significant linear association between diseaseprogression and inhibition of p70S6K activity was reported. In responseto energy stress, the tumor suppressor LKB1 activates AMPK whichphosphorylates the TSC1/2 complex and enables it to inactivate themTOR/p70S6K pathway. Mutations in LKB1 cause Peutz-Jeghers syndrome(PJS), where patients with PJS are 15 times more likely to developcancer than the general population. In addition, ⅓ of lungadenocarcinomas harbor inactivating LKB1 mutations. P70S6K has beenimplicated in metabolic diseases and disorders. It was reported that theabsence of p70S6K protects against age- and diet-induced obesity whileenhancing insulin sensitivity. A role for p70S6K in metabolic diseasesand disorders such as obesity, diabetes, metabolic syndrome, insulinresistance, hyperglycemia, hyperaminoacidemia, and hyperlipidmia issupported based upon the findings.

Compounds described as suitable for p70S6K inhibition are disclosed inWO 03/064397, WO 04/092154, WO 05/054237, WO 05/056014, WO 05/033086, WO05/117909, WO 05/039506, WO 06/120573, WO 06/136821, WO 06/071819, WO06/131835, WO 08/140947, WO 10/093419, WO 10/056563, WO 12/013282, WO12/016001 and WO 12/069146.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide novel compoundsthat modulate kinase activity. This protein kinase modulation includes,but is not limited to, p70S6K inhibition and Akt inhibition useful inthe treatment of hyperproliferative diseases, especially those relatedto the hyperactivity of the above mentioned protein kinases, such ascancer in mammals, with superior pharmacological properties both withrespect to their activities as well as their solubility, metabolicclearance and bioavailability characteristics.

As a result, this invention provides novel, heterocyclic pyrimidinyl andpyridinyl amine compounds and pharmaceutically acceptable salts,solvates or prodrugs thereof, that are kinase inhibitors and useful inthe treatment of the above mentioned diseases. The compounds are definedby Formula (I):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

-   X is N or CH;-   Y is N or CR²;-   E is an unbranched or branched alkyl linker having 1, 2, 3, 4, 5, 6    or 7 C atoms, which may be unsubstituted or mono- or disubstituted    with Hal, OH, CN or NH₂, in which one CH₃ group may be replaced by    Cyc¹, Cyc², CONH₂, CF₃, and in which one, two or three CH₂ groups    may be replaced by —O—, —NH—, or —CO—, and in which one CH group may    be replaced by —N—;-   R¹ is H, CN, CONH₂, Hal, LA, O(LA), Ar, Cyc¹ or Cyc²;-   R² is H, NH₂, Hal or CN;-   Hal is F, Cl, Br or I;-   LA is an unbranched or branched, linear saturated or partially    unsaturated hydrocarbon chain having 1, 2, 3 4, 5 or 6 C atoms,    wherein 1, 2 or 3 H atoms may be replaced by Hal or OH;-   Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton    atoms, which may be unsubstituted or, independently of one another,    mono- or disubstituted by Hal, LA, OH, SH, O(LA), NH₂, NH(LA),    N(LA)₂, NO₂, CN, OCN, COOH, COO(LA), CONH₂, CONH(LA), CON(LA)₂,    NHCO(LA), NHCONH(LA), NHCONH₂, CHO and CO(LA), and/or    monosubstituted by Cyc² or O-Cyc²;-   Cyc¹ is a 3, 4, 5 or 6 membered monocyclic aliphatic homo- or    heterocycle having 0-2 heteroatoms, selected from O, S and N, which    may be mono- or disubstituted by Hal, LA, NH₂, NH(LA), N(LA)₂,    HO(LA)-;-   Cyc² is a 5 or 6 membered monocyclic aromatic homo- or heterocycle    having 0-3 heteroatoms, selected from O, S and N, which may be mono-    or di-substituted by Hal or LA; and-   n is 1 or 2.

In a further preferred embodiment the compounds of the invention conformto Subformulae 1 to 13 of Formula (I), wherein

in Subformula 1

-   X is N,    in Subformula 2-   Y is N or CH,    in Subformula 3-   R¹ is Hal, LA, O(LA), Cyc¹ or Cyc²,    in Subformula 4-   Ar is phenyl or pyridyl, which is unsubstituted or mono- or    disubstituted by Hal, LA or O(LA),    in Subformula 5-   E is a methyl linker which is substituted by aminomethyl, wherein    the amino group of the aminomethyl is unsubstituted, or mono- or    disubstituted by LA, or E is a methyl linker which is substituted by    (azetidin-1-yl)methyl,    in Subformula 6-   Y is CNH₂,-   E is —CH(R³)—NH—CO— or —CO—NH—CH(R³)—,-   R³ is H, CH₂CONH₂ or LA,    in Subformula 7-   X is N,-   Y is N or CH,-   R¹ is Hal, LA, O(LA), Cyc¹ or Cyc²,    in Subformula 8-   X is N,-   Y is N or CH,-   Ar is phenyl or pyridyl, which is unsubstituted or mono- or    disubstituted by Hal, LA or O(LA),    in Subformula 9-   X is N,-   Y is N or CH,-   E is a methyl linker which is substituted by aminomethyl, wherein    the amino group of the aminomethyl is unsubstituted, or mono- or    disubstituted by LA, or E is a methyl linker which is substituted by    (azetidin-1-yl)methyl,    in Subformula 10-   X is N,-   Y is CNH₂,-   E is —CH(R³)—NH—CO— or —CO—NH—CH(R³)—,-   R¹ is Hal, CONH₂, LA, O(LA), Cyc¹ or Cyc²,-   R³ is H, CH₂CONH₂ or LA,    in Subformula 11-   X is N,-   Y is CNH₂,-   E is —CH(R³)—NH—CO— or —CO—NH—CH(R³)—,-   R¹ is Hal, CONH₂, LA, O(LA), Cyc¹ or Cyc²,-   R³ is H, CH₂CONH₂ or LA,-   Ar is phenyl or pyridyl, which is unsubstituted or mono- or    disubstituted by Hal, LA or O(LA),    in Subformula 12-   X is N,-   Y is CNH₂,-   E is —CH(R³)—NH—CO— or —CO—NH—CH(R³)—,-   R³ is H, CH₂CONH₂ or LA,-   Ar is phenyl or pyridyl, which is unsubstituted or mono- or    disubstituted by Hal, LA or O(LA),    in Subformula 13-   X is N,-   Y is N or CH,-   E is a methyl linker which is substituted by aminomethyl, wherein    the amino group of the aminomethyl is unsubstituted, or mono- or    disubstituted by LA, or E is a methyl linker which is substituted by    (azetidin-1-yl)methyl,-   Ar is phenyl or pyridyl, which is unsubstituted or mono- or    disubstituted by Hal, LA or O(LA),-   R¹ is Hal, LA, O(LA), Cyc¹ or Cyc²,    and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof.

In yet further preferred embodiments the substituents designated R¹, inFormula (I), are set out in Table 1.

TABLE 1 Preferred substituents for R¹ in Formula (I):

In other preferred embodiments the substituents designated Ar, inFormula (I), are set out in Table 2.

TABLE 2 Preferred substituents for Ar in Formula (I):

In other preferred embodiments the substituents designated E, in Formula(I), are set out in Table 3.

TABLE 3 Preferred substituents for E in Formula (I):

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. The same applies for enantiomers, e.g., by usingchiral stationary phases. Additionally, enantiomers may be isolated byconverting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of Formula (I) may have one or more centres of chirality.They may accordingly occur in various enantiomeric forms and be inracemic or optically active form. The invention therefore also relatesto the optically active forms (stereoisomers), the enantiomers, theracemates, the diastereomers and hydrates and solvates of thesecompounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3. A method for the resolution of racemates containing estergroups (for example acetyl esters) is the use of enzymes, in particularesterases.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other p70S6K inhibitors. The pharmaceutical compositionsinclude compositions suitable for oral, rectal, topical, parenteral(including subcutaneous, intramuscular, and intravenous), ocular(ophthalmic), pulmonary (nasal or buccal inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, colon, epidermoid, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal,testicular, gynecological, thyroid cancer, melanoma, hematologicmalignancies such as acute myelogenous leukemia, multiple myeloma,chronic myelogneous leukemia, myeloid cell leukemia, glioma, Kaposi'ssarcoma, or any other type of solid or liquid tumors. Preferably, thecancer to be treated is chosen from breast, colorectal, lung, prostateor pancreatic cancer or glioblastoma.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of p70S6K aswell as diseases modulated by the p70S6K cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer andinflammation.

The invention also relates to a compound or pharmaceutical compositionfor treating a disease related to vasculogenesis or angiogenesis in amammal which comprises a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt, prodrugor hydrate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, atherosclerosis, skin diseases such aspsoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy,retinopathy of prematurity and age-related macular degeneration.

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of another anti-cancer therapeutic, wherein the amounts of thecompound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Many anti-cancertherapeutics are presently known in the art. In one embodiment, theanti-cancer therapeutic is a chemotherapeutic selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.In another embodiment the anti-cancer therapeutic is an antibodyselected from the group consisting of bevacizumab, CD40-specificantibodies, chTNT-1/B, denosumab, zanolimumab, IGF1R-specificantibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab,trastuzumab and cetuximab. In yet another embodiment the anti-cancertherapeutic is an inhibitor of another protein kinase, such as Akt, Axl,Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1,Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src,TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK,PDGFR, TAK1, LimK, Flt-3, PDK1 and Erk.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder thatcomprises administering to the mammal an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of a compound of the invention in this combinationtherapy can be determined as described herein. It is believed that thecompounds of the present invention can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/orinhibiting the growth of such cells.

Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention or pharmaceutically acceptable salt or solvate or prodrugthereof, which amount is effective is sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, or solvatein this method can be determined according to the means for ascertainingeffective amounts of such compounds described herein. The invention alsorelates to a method for inhibiting abnormal cell growth in a mammal thatcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.01milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose. For most large mammals, thetotal daily dosage is from about 0.2 milligrams to about 2000milligrams, preferably from about 0.5 milligram to about 1000milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 0.5 milligrams to about 1000 milligrams.These aforementioned dosage regimens may be adjusted to provide theoptimal therapeutic response.

The invention also relates to a set (kit) consisting of separate packsof

a) an effective amount of a compound according to the invention or aphysiologically acceptable salt, solvate or prodrug thereof, and

b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

EXPERIMENTAL SECTION

Some abbreviations that may appear in this application are as follows:

ABBREVIATIONS

Designation ACN acetonitrile ATP Adenosine triphosphate b Broad peak dDoublet DMSO dimethylsulfoxide DIEA N,N-Diisopropylethylamine DTTdithiothreitol EDTA Ethylenediaminetetraacetic acid equiv. equivalentsEt ethyl h hour HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHPLC High pressure liquid chromatography LC/MS Liquid chromatographycoupled to mass spectrometry m multiplet M Molecular ion m/zMass-to-charge ratio Me methyl min minute MS Mass spectrometry N Normal(unit of concentration) NMO 4-methylmorpholine N-oxide NMR NuclearMagnetic Resonance PG Protecting group psi Pounds per square inch qQuartette (or quartet) Rf Retention factor RT Room temperature Rt.Retention time s Singlet Tert Tertiary TEA Triethylamine TFATrifluoroacetic acid THAB Tetrahexylammonium bromide THF TetrahydrofuranUV ultraviolet VIS visible

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples.

Moreover, by utilizing the procedures described herein, in conjunctionwith ordinary skills in the art, additional compounds of the presentinvention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described above. Theamine-free bases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide and potassiumhydroxide, and extraction of the liberated amine-free base into anorganic solvent, followed by evaporation. The amine-free base, isolatedin this manner, can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent, followed byaddition of the appropriate acid and subsequent evaporation,precipitation or crystallization.

The invention will be illustrated, but not limited, by reference to thespecific embodiments described in the following schemes and examples.Unless otherwise indicated in the schemes, the variables have the samemeaning as described above.

Unless otherwise specified, all starting materials are obtained fromcommercially suppliers and used without further purifications. Unlessotherwise specified, all temperatures are expressed in ° C. and allreactions are conducted at room temperature. Compounds were purified byeither silica chromatography or preparative HPLC.

Analytical Methodology

Analytical LC/MS was Performed Using the Following Three Methods:

Method A:

A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rate of 400μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1% formic acid,mobile phase, (B) methanol with 0.1% formic acid; retention times aregiven in minutes. Method details: (I) runs on a Quaternary Pump G1311A(Agilent) with UV/VIS diode array detector G1315B (Agilent) and FinniganLCQ Duo MS detector in ESI+modus with UV-detection at 254 and 280 nmwith a gradient of 15-95% (B) in a 3.2 min linear gradient (II) hold for1.4 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min lineargradient (IV) hold for 2.3 min at 15% (B).

Method B:

A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rate of 1mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05% TFA,mobile phase (B) is ACN with 0.05% TFA; retention times are given inminutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+ mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient (II) hold for 1 minat 85% (B) (III) decrease from 20-85% (B) in a 0.2 min linear gradient(IV) hold for 3.8 min at 20% (B).

Method C:

Gradient: 4.2 min/Flow: 2 ml/min 99:01-0:100 Water+0.1% (Vol.) TFA;Acetonitril+0.1% (Vol.) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min:99:01→0:100; 3.8 to 4.2 min: 0:100; Column: Chromolith PerformanceRP18e; 100 mm long, 3 mm diameter; Wavelength: 220 nm.

Analytical Chiral HPLC

Analytical chiral HPLC was performed using a ChiralPak AD-H column(250×4.6 mm) from Daicel Chemical Industries, Ltd. on an Agilent 1100Series system. The method used a 5.0 μL injection volume, with a flowrate of 1 mL/min of 100% methanol for 15 min at 25° C., and UV-detectionat 254 and 280 nm.

Preparative HPLC

Preparative HPLC was performed using either a Waters Atlantis dC₁₈ OBD™10 μM (30×250 mm) column or a Waters Sunfire Prep C₁₈ OBD 10 μM (30×250mm) column. The columns were used at a flow rate of 60 mL/min on aWaters Prep LC 4000 System equipped with a sample loop (10 mL) and anISCO UA-6 UV/Vis detector. The mobile phase was drawn from two solventreservoirs containing (A) water and (B) HPLC-grade acetonitrile. Atypical preparative run used a linear gradient (e.g., 0-60% solvent Bover 60 min).

The present invention also relates to processes for manufacturing thecompounds of Formula (I) according to the hereinafter described schemesand working examples.

The working examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

Synthetic Schemes Describing Intermediates and End Product Compounds

Pyrimidine chloride intermediates were either commercially available orprepared according to the synthetic routes outlined in Scheme 1 andScheme 2.

Formamidine acetate was reacted with diethyl-ethylmalonate in thepresence of sodium ethoxide in dry ethanol to yield5-ethylpyrimidine-4,6-diol, which was converted to 4,6-Dichloro-5-ethylpyrimidine by POCl3 in the presence of TEA in toluene.4,6-Dichloro-5-ethylpyrimidine was then reacted with aqueous ammonia inn-butanol at 100° C. to afford 4-amino-5-ethyl-6-chloropyrimidine.

4-amino-6-chloropyrimidin-5-ol was reacted with alkylated regents toprovide the desired pyrimidine chloride intermediates.

The pyrimidine chloride intermediates 1 reacted with secondary amines 2in the presence of base to provide compounds 3. A Suzuki coupling isperformed if R1 is bromo of compounds 3 to afford compounds 4.

Tert-butyl-4 oxopiperidone-1-carboxylate was treated with2-(4-(trifluoromethyl)phenyl)acetonitrile under basic condition to formcompound 5. Hydrogenation of compound 5 by using Pd(OH)2 as catalyst toreduce the double bond and Raney Ni as catalyst to convert cyanide toamine, followed by de-Boc generated intermediate 6, which was couplingwith 5-bromo-6-chloropyrimidin-4-amine to yield compound 7. The primaryamine 7 was protected by Boc to give intermediate 8, which was performeda Suzuki coupling, followed by Boc deprotection to affod compounds 9.

5-(4-fluorophenyl)-6-(piperazin-1-yl)pyrimidin-4-amine was reacted witharyl aldehydes or ketones under reductive amination condition togenerate desired compounds 10.

The displacement of bromides 11 with secondary amines 12 providedketones 13, which was reduced to alcohols 14. Alcohols 14 were convertedto the corresponding chlorides 15 by thionyl chloride. Chlorides 15 werereacted with piperazine intermediates 16 to afford the desired theproducts 17.

5-Bromo-6-chloro-pyrimidine-4-ylamine was reacted with secondary amines18 in the presence of base to provide the bromide intermediates 19. ASuzuki coupling is performed with the bromide intermediates 19 andboronic acid or ester to afford the ketone intermediates 20. Reductiveamination of the ketone intermediates 20 with amines in the presence ofsodium cyanoborohydride provided the desired products 21. Reduction ofketon intermediates 20 with sodium borohydride gave the second alcohols22, which can be further converted to compounds 23 by alkylating withchlorides. Compounds 25 were obtained via their chlorides intermediates24 from the corresponding alcohols 22.

The Strecker reaction with 4-heterocyclic-6-aminopyrimidine 26,aryl-aldehydes, and trimethylsilyl cyanide provided the nitriles 27.Reduction of the nitriles afforded the primary amine as desired products28.

5-Bromo-6-chloro-pyrimidine-4-ylamine was reacted with secondary amines29 in the presence of base to provide the bromides 30. A Suzuki couplingwas then performed with the bromides 30 and boronic acid or ester toafford compounds 31.

Amide coupling of1-(tert-butoxycarbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylicacid with amines 32 followed by Boc deprotection generated amineintermediate 33, which was reacted with 6-amino-5-substituted-4-chloropyrimidines provided compounds 34. A Suzuki coupling was then performedif R1 of compounds 34 is bromine to afford compounds 35.

Examples

Examples 136 and 209-213 have been purposely omitted given adiscontinuity in the clerical numbering of the compounds as described inthe instant application.

Examples (1) to (50) were prepared according to Scheme 3.

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine(“1”)

Intermediate (1.1):2-Piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylamine hydrochloride

A mixture of4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (185 mg; 0.5 mmol; 1.0 eq.) and 4M hydrogenchloride in dioxane (1.8 ml; 7.4 mmol; 15 eq.) in Methanol (3.00 ml) wasstirred at room temperature overnight. Ether was added to the reactionmixture. The precipitate was filtered, washed with ether and dried toyield 2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylaminehydrochloride salt as off-white solid in 67% yield.

A mixture of 5-bromo-6-chloropyrimidin-4-amine (51.6 mg; 0.24 mmol, 1.0eq.), intermediate (1.1) (100.0 mg; 0.24 mmol, 1.0 eq.) and potassiumcarbonate (97.5 mg; 0.7 mmol; 3.0 eq.) in DMSO (2.00 ml) was heated at60° C. for 8 h. The reaction mixture was purified by pre-HPLC (Waters,basic condition) to afford the title compound as white solid in 70%yield. LC-MS: (M+1=445, obsd.=445).

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“2”)

A mixture of6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine(110.00 mg; 0.25 mmol; 1.0 eq.), (4-fluorophenyl)boronic acid (103.7 mg;0.74 mmol; 3.0 eq.), palladium(2+) acetate (5.5 mg; 0.02 mmol; 0.1 eq.),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (20.2 mg; 0.05 mmol;0.2 eq.) and cesium carbonate (241.4 mg; 0.74 mmol; 3.0 eq.) in dioxane(5.00 ml) and water (0.50 ml) in a sealed tube was stirred at 100° C.overnight. The crude was purified by Reverse Phase chromatography(Waters, basic condition) to afford the title compound as a white solidin 75% yield. LC-MS: (M+1=461, obsd.=461).

6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“3”)

The title compound was obtained via SFC chiral separation of Example(2). LC-MS: (M+1=461, obsd.=461).

6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“4”)

The title compound was obtained via SFC chiral separation of Example(2). LC-MS: (M+1=461, obsd.=461).

6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-bromo-pyrimidin-4-ylamine(“5”)

The title compound was prepared in an analogous manner as Example (1) byusing 4-[2-amino-1-phenylethyl]-piperazine-1-carboxylic acid tert-butylester instead of4-[2-amino-1-(4-trifluoromethylphenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester. LC-MS: (M+1=377, obsd.=377).

6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“6”)

The title compound was prepared in an analogous manner as Example (2) byusing6-{4-[2-amino-1-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamineinstead of6-{4-[2-amino-1-(4-trifluoromethylphenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine.LC-MS: (M+1=393, obsd.=393).

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“7”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=433, obsd.=433).

(S)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“8”)

The title compound was obtained by chiral separation with SFC column ofExample (7). LC-MS: (M+1=433, obsd.=433).

(R)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“9”)

The title compound was obtained by chiral separation with SFC column ofExample (7). LC-MS (M+1=433, obsd.=433).

5-(4-fluorophenyl)-6-(4-(2-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)-phenyl)-ethyl)-piperazin-1-yl)-pyrimidin-4-amine(“10”)

Intermediate (10.1):1-(2-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazinehydrochloride salt

In a dry microwave vial was added4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (160.0 mg; 0.43 mmol; 1.0 eq.), Potassiumcarbonate (296.1 mg; 2.14 mmol; 5.0 eq.), 1,4-Dibromo-butane (55.9 μl;0.47 mmol; 1.1 eq.) and. The vial was capped and connected to a vacuumfor 10 sec. before it was influx with N2. The white turbid mixture wasstirred at 83° C. overnight. No SM was detected. The crude mixture wasfiltered, concentrated and purified via 10 g KPNH column to afford the68 mg Boc protected Intermediate (8.1). To a 25 mL flask containing theobtained Boc protected title compound in MeOH (5 mL) was added hydrogenchloride (0.8 ml; 1.61 mmol; 10.0 eq.) at 0° C. slowly. The obtainedsolution was warmed up to room temperature and stirred overnight. LCMSdidn't detect any SM. The crude mixture was concentrated and directedused in the next step. LC-MS: (M+1=328, obsd.=328).

Intermediate (10.2):5-bromo-6-(4-(2-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)phenyl)-ethyl)piperazin-1-yl)pyrimidin-4-amine

Intermediate (10.2) was prepared in an analogous manner as Example (1)using Intermediate (10.1). LC-MS: (M+1=499, obsd.=499).

Example (10) was prepared in an analogous manner as Example (2) usingIntermediate (10.2). LC-MS: (M+1=515, obsd.=515).

5-bromo-6-(4-(2-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“11”)

Intermediate (11.1):1-(2-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazinehydrochloride salt

Intermediate (11.1) (315 mg) was prepared in an analogous manner asIntermediate (10.1) using 1,5-dibromo-pentane (120.38 μl; 0.88 mmol; 1.1eq.) instead of 1,4-dibromo butane. The concentrated crude product wasdirectly used in the next step. LC-MS: (M+1=342, obsd.=342).

Example (11) was prepared in an analogous manner as Example (1) usingIntermediate (9.1). LC-MS: (M+1=513, obsd.=513).

5-(4-Fluoro-phenyl)-6-{4-[2-piperidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“12”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=529, obsd.=529).

5-(4-Fluoro-phenyl)-6-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-pyrimidin-4-ylamine(“13”)

Intermediate (13.1):4-(6-Amino-5-bromo-pyrimidin-4-yl)-piperazine-1-carboxylic acidtert-butyl ester

Intermediate (13.1) was prepared in an analogous manner as Example (1)using Piperazine-1-carboxylic acid tert-butyl ester instead of4-[2-amino-1-(4-trifluoromethylphenyl)-ethyl]-piperazine. LC-MS:(M+1=358, obsd.=358).

Intermediate (13.2):4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester

Intermediate (13.2) was prepared in an analogous manner as Example (2).LC-MS: (M+1=374, obsd.=374).

Intermediate (13.3):5-(4-Fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine

The mixture of the Intermediate (10.2) (370 mg; 1 mmol; 1.0 eq.), 4Mhydrogen chloride in dioxane (2.5 mL, 10 mmol, 10 eq.) in MeOH (2.0 ml)is stirred at room temperature for 3 h. The reaction mixture is dilutedwith ether. The precipitate was filtered and washed with ether to affordthe Intermediate (10.3) as HCl salt. LC-MS: (M+1=274, obsd.=274).

The mixture of Intermediate (13.3) (60.0 mg; 0.22 mmol; 1.0 eq.),1-bromomethyl-4-trifluoromethylbenzene (52.48 mg; 0.22 mmol; 1.00 eq.)and DIPEA (0.04 ml; 0.26 mmol; 1.2 eq.) in THF (2.0 ml) is stirred atroom temperature overnight. The reaction mixture was concentrated andpurified by pre-HPLC (Waters, basic condition) to yield the titlecompound as a white solid in 76% yield. LC-MS: (M+1=432, obsd.=432).

5-bromo-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“14”)

The title compound was prepared in an analogous manner as Example (1) byusingN,N-dimethyl-2-(piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanamineinstead of 2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylamine.LC-MS: (M+1=474, obsd.=474)

6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“15”)

The title compound was prepared in an analogous manner as Example (2) byusing 5-bromo-6-(4-(2-(dimethylamino)-1-(4(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine insteadof6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)-piperazin-1-yl)-5-bromopyrimidin-4-amine.LC-MS: (M+1=489, obsd.=489)

(S)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“16”)

The title compound was obtained via SFC chiral separation of Example(15). LC-MS: (M+1=489, obsd.=489).

(R)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“17”)

The title compound was obtained via SFC chiral separation of Example(15). LC-MS: (M+1=489, obsd.=489).

2-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide(“18”)

The title compound was prepared in an analogous manner as Example (2) byusing2-(4-(6-amino-5-bromopyrimidin-4-yl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamideinstead of6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-bromopyrimidin-4-amine.LC-MS: (M+1=546, obsd.=546)

6-(4-(2-amino-1-(4-(trifluoromethyl)-phenyl)ethyl)piperazin-1-yl)-5-vinylpyrimidin-4-amine(“19”)

The title compound was prepared in an analogous manner as Example (2) byusing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane instead of4-fluorophenyl boronic acid. LC-MS: (M+1=394, obsd.=394)

5-(6-aminopyridin-3-yl)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)-phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“20”)

The title compound was prepared in an analogous manner as Example (15)by using (6-aminopyridin-3-yl) boronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=487, obsd.=487)

6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-vinylpyrimidin-4-amine(“21”)

The title compound was prepared in an analogous manner as Example (15)by using 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane instead of4-fluorophenyl boronic acid. LC-MS: (M+1=421, obsd.=421)

2-(4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)-piperazin-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol(“22”)

The title compound was prepared in an analogous manner as Example (15)by using2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-olinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=529, obsd.=529)

Methyl4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)benzoate(“23”)

The title compound was prepared in an analogous manner as Example (15)by using methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=529, obsd.=529)

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclohex-1-en-1-yl)pyrimidin-4-amine(“24”)

The title compound was prepared in an analogous manner as Example (2) byusing methyl2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane insteadof 4-fluorophenyl boronic acid. LC-MS: (M+1=447, obsd.=447)

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclopent-1-en-1-yl)pyrimidin-4-amine(“25”)

The title compound was prepared in an analogous manner as Example (2) byusing 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 4-fluorophenyl boronic acid. LC-MS: (M+1=433, obsd.=433)

4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)benzoicacid (“26”)

In a round bottle flask containing4-(4-Amino-6-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-benzoicacid methyl ester trifluoroacetic acid (36.00 mg; 0.06 mmol; 1.00 eq.)in THF (2.00 ml) and water (2.00 ml) was added 1 N lithium hydroxidemonohydrate water solution. The mixture was stirred at rt for 4 h beforeit was concentrated and purified with waters prep-HPLC. LC-MS: (M+1=515,obsd.=515)

6-(4-(2-(azetidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“27”)

In a microwave vial containing1-[2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-azetidine (32.26 mg;0.12 mmol; 1.00 eq.) from last step in acetonitrile (2.00 ml) was added5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (33.43 mg; 0.12mmol; 1.00 eq.), followed by DIPEA (0.06 ml; 0.37 mmol; 3.00 eq.). Theclear solution was stirred at 60° C. overnight and then 75° C. for 3 hbefore the mixture was concentrated and purified with waters pre-HPLC.LC-MS: (M+1=501, obsd.=501)

5-Cyclopropyl-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“28”)

In a microwave vial containing5-bromo-6-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(84.00 mg; 0.18 mmol; 1.00 eq.) in toluene (3.00 ml; 28.23 mmol; 159.07eq.) and water (0.30 ml; 16.65 mmol; 93.84 eq.) was added palladium(ii)acetate (3.98 mg; 0.02 mmol; 0.10 eq.), potassiumcyclopropyltrifluoroborate (52.52 mg; 0.35 mmol; 2.00 eq.), cesiumcarbonate (127.21 mg; 0.39 mmol; 2.20 eq.) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.54 mg; 0.04 mmol;0.20 eq.). The mixture was microwaved at 125° C. for 30 min before itwas filtered the desired product was purified with Waters prep-HPLC.LC-MS: (M+1=435, obsd.=435)

5-Bromo-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“29”)

The title compound was prepared as a white solid in 67.7% yield in ananalogous manner as Example (1) by using 1-[(1-methyl-1h-imidazol-2-yl)-phenyl-methyl]-piperazine instead of2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethylamine. LC-MS:(M+1=429.3, obsd.=429.2).

5-(4-Fluoro-phenyl)-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“30”)

The title compound was prepared as a white solid in 79% yield in ananalogous manner as Example (2). LC-MS: (M+1=443.5, obsd.=444.3).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-methoxypyrimidin-4-amine(“31”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=397, obsd.=397).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-ethoxypyrimidin-4-amine(“32”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=411, obsd.=411).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine(“33”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=465, obsd.=465).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(benzyloxy)pyrimidin-4-amine(“34”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=473, obsd.=473).

(35)4-amino-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-ol (“35”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=483, obsd.=483).

4-Amino-6-{4-[2-amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine-5-carbonitrile(“36”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=392, obsd.=392).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrrol-3-yl)pyrimidin-4-amine(“37”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=432, obsd.=432).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“38”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=434, obsd.=434).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine(“39”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=461, obsd.=461).

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“40”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=447, obsd.=447).

6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“41”)

The title compound was isolated by the SFC chiral separation of Example(40). LC-MS: (M+1=447, obsd.=447)

6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“42”)

The title compound was isolated by the SFC chiral separation of Example(40). LC-MS: (M+1=447, obsd.=447)

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamine(“43”)

The title compound was prepared in an analogous manner as Example (2).LC-MS: (M+1=447, obsd.=447).

3-[2-{4-[6-Amino-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-(4-trifluoromethyl-phenyl)-ethylamino]-2,3-dimethyl-butan-2-ol(“44”)

The title compound was obtained as the by-product of Example (43).LC-MS: (M+1 10=547, obsd.=547).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-((3-fluoroazetidin-1-yl)methyl)pyrimidin-4-amine(“45”)

To 3-fluoro-azetidine hydrochloride (17.64 mg; 0.12 mmol; 1.05 eq.) in 1ml of DCE was added DIEA (0.04 ml; 0.23 mmol; 2.00 eq.). After stirredat RT for 10 mins,[2-[4-(6-amino-5-formyl-pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethyl]-carbamicacid benzyl ester (60.00 mg; 0.11 mmol; 1.00 eq.) was added, followed bysodium p-triacetoxyborohydride (72.18 mg; 0.34 mmol; 3.00 eq.). Thereaction mixture was stirred overnight at RT. Poured the reactionsolution to EA, washed with 5% sodium bicarbonate and brine. The organiclayer was separated, dried and concentrated to afford the intermediate.

The above intermediate was dissolved in 1 ml of methanol, 70 mg 10% Pd/Cwas added and then 100 mg of ammonium formate. The resulting reactionmixture was stirred at 60° C. for 1 hr. The crude was purified bypre-HPLC to yield the title compound (10 mg, yield 15%). LC-MS:(M+1=454, obsd.=454).

5-Bromo-6{4-(4-chlorobenzyl)-piperidin-1-yl}pyrimidin-4-amine (“46”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=382, obsd=382)

5-Bromo-6{4-(4-trifluoromethylbenzyl)-piperidin-1-yl}pyrimidin-4-amine(“47”)

The title compound was prepared in an analogous manner as Example (1).LC-MS (M+1=416, obsd=416)

5-(4-Fluorophenyl)-6{4-(4-trifluoromethylbenzyl)-piperidin-1-yl}pyrimidin-4-amine(“48”)

The title compound was prepared in an analogous manner as Example (2).LC-MS (M+1=431, obsd=431)

5-(4-Fluorophenyl)-6{4-(4-chlorobenzyl)-piperidin-1-yl}pyrimidin-4-amine(“49”)

The title compound was prepared in an analogous manner as Example (2).LC-MS (M+1=398, obsd=398)

5-(4-Fluorophenyl)-6{4-(4-(4-fluorophenyl)benzyl)-piperidin-1-yl}pyrimidin-4-amine(“50”)

The title compound was prepared in an analogous manner as Example (2).LC-MS (M+1=457, obsd=457)

Examples (51) to (59) were prepared according to Synthetic Scheme 4.

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine(“51”)

Intermediate (51.1) tert-butyl4-(cyano(4-(trifluoromethyl)phenyl)methylene)piperidine-1-carboxylate

To the solution of 4-(trifluoromethyl)phenylacetonitrile (2560.9 mg;13.83 mmol; 1.06 eq.) in ethanol (50 mL), 21% sodium ethoxide (5.70 ml;15.27 mmol; 1.17 eq.) in ethanol was added dropwise at RT. After stirredfor 30 min, a solution of 1-boc-4-piperidone (2600.00 mg; 13.05 mmol;1.00 eq.) in ethanol (10 mL) was added slowly. The reaction mixture wasstirred at room temperature for 4 h. The reaction was quenched with 50mL of saturated aqueous NH4Cl and concentrated to half volume. Theaqueous solution was extracted with ether three times. The combinedorganic extracts were washed with brine, dried and then concentrated togive the crude product, which was purified by Biotage chromatographywith EtOAc/Hexane (5-30%) to yield the desired product as light yellowsolid (3200.00 mg, yield 66.9%).

Intermediate (51.2)2-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine hydrochloridesalt

A solution of Intermediate (51.1) (2000.0 mg; 5.46 mmol; 1.00 eq.) in 50ml of methanol was surged on H-Qube through 20% Pd(OH)₂ cartridge at 1.5ml/min and RT for one cycle. LCMS showed a clean product as tert-butyl4-(cyano(4-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxylate. 10ml of 7.0N NH₃ in methanol was added to the above solution and thesolution was then placed on H-Qube through Raney Ni column as cartridgeat 1.5 ml/min and 45° C. for one cycle. LCMS showed clean reaction ofreducing nitrile. The reaction mixture was concentrated to affordtert-butyl4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)-piperidine-1-carboxylate,which was added 10 ml of 4.0M HCl in dioxane and stirred at RT for 4 hr.The precipitate was collected by filtration to yield the title compoundas white solid (1600 mg, yield 77.7%). LC-MS: (M+1=273, obsd.=273).

A mixture of 5-bromo-6-chloropyrimidin-4-amine (317.78 mg; 1.45 mmol;1.00 eq.), Intermediate (51.2) (500.00 mg; 1.45 mmol; 1.00 eq.) andpotassium carbonate (600.48 mg; 4.34 mmol; 3.00 eq.) in DMSO (5.00 m)was heated at 60° C. for 14 h. The reaction mixture was purified bypre-HPLC (Waters, basic condition) to afford the title compound. LC-MS:(M+1=444, obsd.=444).

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“52”)

The title compound was prepared in an analogous manner as Example (2) byusing of6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamineinstead of6-{4-[2-amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine.LC-MS: (M+1=460, obsd.=460).

6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“53”)

The title compound was obtained via SFC chiral separation of Example(52). LC-MS: (M+1=460, obsd.=460).

6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“54”)

The title compound was obtained via SFC chiral separation of Example(52). LC-MS: (M+1=460, obsd.=460).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“55”)

Intermediate (55.1) tert-butyl(2-(1-(6-amino-5-bromopyrimidin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)carbamate

A mixture of6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-bromopyrimidin-4-amine(1700 mg; 3.84 mmol; 1.00 eq.) and di-tert-butyl dicarbonate (837.62 mg;3.84 mmol; 1.00 eq.) in THF (50 ml) was stirred at RT overnight. Thereaction mixture was concentrated and subjected to SNAP column (100 g),eluted with 30-80% ethyl acetate in hexan to yield the title compound(1400 mg, yield 67%). LC-MS: (M+1=544, obsd=543/544).

A mixture of Intermediate (55.1) (280.00 mg; 0.51 mmol; 1.00 eq.),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (226.93 mg; 0.77 mmol; 1.50 eq.) and cesiumcarbonate (335 mg, 1.03 mmol, 2.0 eq.) in dioxane (3 ml) and water (0.25ml) was degas, and then bis(tri-t-butylphosphine)palladium(0) (39.43 mg;0.08 mmol; 0.15 eq.) added. The resulting mixture was stirred at 50° C.overnight. The reaction mixture was worked up and purified by SNAPcolumn, eluted with 0-10% methanol in DCM to give tert-butyl4-(4-amino-6-(4-(2-((tert-butoxycarbonyl)amino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazole-1-carboxylate(280 mg, yield 86%), which was added 4 ml of methanol and 3 ml of 4.0MHCl in dioxane and stirred at RT for 3 hr. The reaction mixture wasconcentrated to afford the title compound in quantitative yield. LC-MS:(M+1=432, obsd.=432).

(S)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“56”) (Shown in One of Enantiomer, Absolute Chirality is Unknown)

The title compound was obtained by chiral separation with SFC column ofExample (55). LC-MS (M+1=432, obsd.=432).

(R)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“57”) (Shown in One of Enantiomer, Absolute Chirality is Unknown)

The title compound was obtained by chiral separation with SFC column ofExample (55). LC-MS (M+1=432, obsd.=432).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(“58”)

The title compound was prepared in an analogous manner as Example (55).LC-MS (M+1=446, obsd.=446).

6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“59”)

The title compound was prepared in an analogous manner as Example (55).LC-MS (M+1=433, obsd.=433).

Examples (60) to (63) were prepared according to Synthetic Scheme 5.

2-((4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-4,5-dichlorophenol(“60”)

A reaction mixture of5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (400.0 mg; 1.46mmol; 1.00 eq.), 4,5-dichloro-2-hydroxy-benzaldehyde (279.5 mg; 1.46mmol; 1.00 eq.), Acetic acid (87.8 mg; 1.46 mmol; 1.00 eq.) and sodiumtriacetoxy borohydride (926.1 mg; 4.39 mmol; 3.00 eq.) in DCE (10 ml)was stirred overnight at RT. The reaction solution was diluted with DCMand washed with brine. The organic layer was dried and concentrated,which was added 10 ml of ether and stirred for mins. The precipitate wasfiltered to afford the title and white off solid (528 mg, yield 80.5%).LC-MS: (M+1=448, obsd.=448/450).

2-(1-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)ethyl)-5-chlorophenol(“61”)

The title compound was prepared in an analogous manner as Example (60)by 5-(4-fluorophenyl)-6-(piperazin-1-yl)pyrimidin-4-amine reacted with1-(4-chloro-2-hydroxyphenyl)ethanone. LC-MS: (M+1=428, obsd.=428/430).

6-(4-(2-(azetidin-3-yloxy)-4,5-dichlorobenzyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“62”)

A reaction mixture of2-{4-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-ylmethyl}-4,5-dichloro-phenol(80.0 mg; 0.18 mmol; 1.00 eq.), 3-iodo-azetidine-1-carboxylic acidtert-butyl ester (60.6 mg; 0.21 mmol; 1.20 eq.) and cesium carbonate(116.2 mg; 0.36 mmol; 2.00 eq.) in DMF (1 ml) was stirred at 90° C.overnight. The reaction solution was poured to water and extracted withethyl acetate, The separated organic layer was washed with brine, driedand concentrated, which was then dissolved in methanol (1 ml) followedby adding 4.0 M HCl in dioxane (2 ml) and stirred at RT overnight. Thereaction mixture was concentrated and purified by Waters prep-HPLC(acidic condition) to a yield the title compounds (37 mg, yield 33.6%).LC-MS: (M+1=504, obsd.=504/506).

6-(4-{1-[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-ethyl}-piperazin-1-yl)-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“63”)

The title compound was prepared in an analogous manner as Example (62)using2-((4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-5-chlorophenol.LC-MS (M+1=483, obsd.=483).

Examples (64) to (137) were prepared according to Synthetic Scheme 6.

5-(4-Fluorophenyl)-6{4-[1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“64”)

Intermediate (64.1): 1-(3-Fluoro-phenyl)-2-piperidin-1-yl-ethanone

A mixture of 2-bromo-1-(3-fluoro-phenyl)-ethanone (5.0 g; 23.04 mmol;1.0 eq.), piperidine (2.30 ml; 23.04 mmol; 1.0 eq.) and DIEA (4.89 ml;27.65 mmol; 1.20 eq.) in CHCl₃ (100 mL) was heated for reflux overnight.The mixture was partitioned between CHCl₃ and saturated aqueous NaHCO₃.The separated organic layer was dried over MgSO₄, filtered andconcentrated. The residue was purified through flash chromatography onsilica gel to afford the title compound. LC-MS: 222 (M+H).

Intermediate (64.2): 1-(3-Fluoro-phenyl)-2-piperidin-1-yl-ethanol

To a solution of 1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethan Intermediate(64.1) (1.50 g; 6.78 mmol; 1.00 eq.) in MeOH (15 mL) was added sodiumborohydride (0.38 g; 10.17 mmol; 1.50 eq.) and 1 mL of water and 1 dropof 10% NaOH. Then the mixture was stirred at 50° C. for 5 hours. Thereaction mixture was partitioned between CHCl₃ and water. The organiclayer was separated, dried over MgSO₄ and concentrated. The residue waspurified through flash chromatography on silica gel to yield1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethanol. LC-MS: 224 (M+H).

Intermediate (64.3): 1-[2-Chloro-2-(3-fluoro-phenyl)-ethyl]-piperidine

To a solution of Intermediate (64.2) (2.00 g; 8.96 mmol; 1.00 eq.) inDCM (20 mL) was added thionyl chloride (3.27 ml; 44.79 mmol; 5.00 eq.)dropwise and the mixture was stirred at room temperature overnight.After removed the solvent, the solid was suspended in EtOAc and thesolid was filtered and dried to yield the title compound. LC-MS: 242(M+H).

A mixture of Intermediate (64.3) (50.00 mg; 0.21 mmol; 1.00 eq.),5-(4-fluorophenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (80.12 mg; 0.21mmol; 1.00 eq.) and DIEA (0.18 ml; 1.03 mmol; 5.00 eq.) in acetonitrile(5 mL) was stirred at 70° C. overnight. The mixture was purified throughreverse phase HPLC to provide the title compound. LC-MS: (M+1=479,obsd.=479).

5-(4-Fluorophenyl)-6{4-[1-(3-trifluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“65”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=529, obsd.=529).

5-(4-Fluorophenyl)-6{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“66”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=514, obsd.=514).

5-(4-Fluorophenyl)-6{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“67”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=479, obsd.=479).

5-Bromo-6{4-[1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“68”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=463, obsd=463)

5-Bromo-6{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“69”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=499, obsd=499)

5-Bromo-6{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“70”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=513, obsd=513)

6-{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“71”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=435, obsd=435)

5-Bromo-6{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“72”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=463, obsd=463)

6-{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“73”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=421, obsd=421)

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-fluoro-pyrimidin-4-ylamine(“74”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=385, obsd=385)

5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“75”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=465, obsd=465)

6-{4-[1-(3-fluorophenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“76”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=385, obsd=385)

5-Bromo-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“77”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=449, obsd=449)

6-{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine“78”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=371, obsd=371)

6-{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“79”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=485, obsd=485)

6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-chloro-pyrimidin-4-ylamine(“80”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=401, obsd=401)

5-Chloro-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“81”)

The title compound was prepared in an analogous manner as Example (64).LC-MS (M+1=405, obsd=405)

(R)5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“82”)

The title compound was prepared in a chiral separation of Example (75).LC-MS (M+1=465, obsd=465)

(S)-5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“83”)

The title compound was prepared in a chiral separation of Example (75).LC-MS (M+1=465, obsd=465)

6-{4-[2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“84”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation Example (3). LC-MS: (M+1=423,obsd.=423)

4-(1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“85”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=430, obsd.=430)

4-(1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“86”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=463, obsd.=463)

6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“87”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=423, obsd.=423)

4-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“88”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=430, obsd.=430)

4-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“89”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=463, obsd.=463)

6-{4-[2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“90”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=451, obsd.=451)

3-((R)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“91”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=430, obsd.=430)

6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“92”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=481, obsd.=481)

6-{4-[(R)-2-Azetidin-1-yl-1-(4-methanesulfonyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“93”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=483, obsd.=483)

6-{4-[(R)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“94”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=491, obsd.=491)

6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“95”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=453, obsd.=453)

4-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“96”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=491, obsd.=491)

3-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“97”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=430, obsd.=430)

6-{4-[(S)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“98”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=491, obsd.=491)

6-{4-[2-Azetidin-1-yl-1-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“99”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=491, obsd.=491)

6-{4-[2-Azetidin-1-yl-1-(2,3-difluoro-4-methyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“100”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=430, obsd.=430)

6-{4-[2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“101”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=491, obsd.=491)

6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“102”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=451, obsd.=451)

6-{4-[(R)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“103”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=451, obsd.=451)

6-{4-[(R)-2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“104”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=481, obsd.=481)

6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“105”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=481, obsd.=481)

4-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“106”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=458, obsd.=458)

6-{4-[(R)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“107”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=463, obsd.=463)

6-{4-[(S)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“108”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=463, obsd.=463)

6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“109”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=453, obsd.=453)

4-((S)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“110”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=491, obsd.=491)

4-((R)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“111”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=491, obsd.=491)

6-{4-[3-Azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“112”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=482, obsd.=482)

6-{4-[4-Azetidin-1-yl-1-(4-chloro-phenyl)-butyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“113”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=496, obsd.=496)

6-{4-[2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“114”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=507, obsd.=507)

6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“115”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=554, obsd.=554)

6-{4-[2-Azetidin-1-yl-1-(4-imidazol-1-yl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“116”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=499, obsd.=499)

[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid ethyl ester (“117”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=560, obsd.=560)

6-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-3H-benzothiazol-2-one(“118”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=506, obsd.=506)

[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid ethyl ester (“119”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=545, obsd.=545)

6-{4-[2-Azetidin-1-yl-1-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“120”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=491, obsd.=491)

6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“121”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=457, obsd.=457)

6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“122”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=459, obsd.=459)

6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“123”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=487, obsd.=487)

6-{4-[2-Azetidin-1-yl-1-(2,3-difluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“124”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=441, obsd.=441)

3-((S)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“125”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=458, obsd.=458)

6-{4-[2-Azetidin-1-yl-1-(2,3-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“126”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=474, obsd.=474)

6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“127”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=491, obsd.=491)

6-{4-[2-Azetidin-1-yl-1-(4-methanesulfonyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“128”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=511, obsd.=511)

3-((R)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“129”)

The title compound was prepared in an analogous manner as Example (64)then isolated by the SFC chiral separation. LC-MS: (M+1=458, obsd.=458)

[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(3-cyano-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid methyl ester (“130”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=502, obsd.=502)

6-{4-[2-Azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“131”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=474, obsd.=474)

6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“132”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=507, obsd.=507)

6-{4-[2-Azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“133”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=569, obsd.=569)

6-{4-[2-Azetidin-1-yl-1-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“134”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=507, obsd.=507)

6-{4-[2-Azetidin-1-yl-1-(3-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“135”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=457, obsd.=457)

6-{4-[2-Azetidin-1-yl-1-(2-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“137”)

The title compound was prepared in an analogous manner as Example (64).LC-MS: (M+1=457, obsd.=457)

Examples (138) to (151) were prepared according to Synthetic Scheme 7.

1-6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperidin-4-yl-4-(chlorophenyl)methanol(“138”)

Intermediate (138.1):[1-(6-Amino-5-bromo-pyrimidin-4-yl)-piperidin-4-yl]-(4-chloro-phenyl)-methanone

The mixture of 5-bromo-6-chloro-pyrimidine-4-ylamine (2.0 g, 9.59 mmol,1.0 eq), 4-chlorophenyl-piperidin-4-yl-methanone (2.36 g, 10.55 mmol,1.10 eq) and potassium carbonate (6.63 g, 47.97 mmol, 5.0 eq) in DMF (5mL) was stirred at 50° C. overnight. After pouring the reaction mixtureto water, the precipitate was collected to give Intermediate (138.1).LC-MS (M+1: 396, obsd: 396).

Intermediate (138.2):{1-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperidin-4-yl}-(4-chloro-phenyl)-methanone

A mixture of Intermediate (84.1) (2.0 g, 5.05 mmol, 1.0 eq),4-fluorophenyl boronic acid (707.24 mg, 5.05 mmol, 1.0 eq), palladiumacetate (113.48 mg, 0.5 mmol, 1.0 eq), s-phosphine (415.01 mg, 1.01mmol, 0.2 eq), and cesium carbonate (3293.76 mg, 10.11 mmol, 2.0 eq) in1,4-dioxane (10 mL) and water (1.0 mL) in the sealed vial was stirred at50° C. overnight. After usual workup, the crude was purified throughpreparative HPLC purification to yield Intermediate (138.2). LC-MS (M+1:411, obsd: 411).

To a solution of Intermediate (138.2) (500 mg, 1.22 mmol, 1.0 eq) inmethanol (15 mL) was added sodium borohydride (70 mg, 1.85 mmol, 1.5eq). The mixture was stirred overnight. After concentration, the mixturewas diluted with ethyl acetate and washed with brine. The organic layerwas dried over MgSO₄, concentrated and purified by flash chromatographyon silicon gel to afford the title compound. MS-LC (M+1: 414, obsd:414).

1-6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperidin-4-yl-4-(4-fluorophenyl)phenyl)methanol(“139”)

The title compound was prepared in an analogous manner as Example (138).LC-MS (M+1=473, obsd=473)

1-6-amino-5-(4-fluoropheny)pyrimidin-4-yl)piperidin-4-yl-4-(fluorophenyl)methanol(“140”)

The title compound was prepared in an analogous manner as Example (138).LC-MS (M+1=397, obsd=397)

1-6-amino-5-(vinylpyrimidin-4-yl)piperidin-4-yl-4-(fluorophenyl)methanol(“141”)

The title compound was prepared in an analogous manner as Example (138).LC-MS (M+1=329, obsd=329)

5-(4-Fluorophenyl)-6{4-amino(4-chlorophenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“142”)

To a solution of Intermediate (138.2) (150 mg, 0.38 mmol, 1.0 eq) andammonium acetate (337 mg, 4.3 mmol, 12 eq.) in methanol (5 mL) was addedsodium cyanoborohydride (1.90 mmol, 5 eq). The mixture was refluxed for2 days. After concentration, the mixture was diluted with ethyl acetateand washed with brine. The organic layer was dried over MgSO₄,concentrated and purified through flash chromatography on silicon gel toafford the title compound. LC-MS (M+1=413, obsd=413)

5-(4-Fluorophenyl)-6{4-amino(4-fluorophenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“143”)

The title compound was prepared in an analogous manner as Example (142).LC-MS (M+1=396, obsd=396)

5-(4-Fluorophenyl)-6{4-amino(4-(4-fluorophenyl)phenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“144”)

The title compound was prepared in an analogous manner as Example (142).LC-MS (M+1=472, obsd=472)

6-(4-((cyclopentylamino)(4-fluorophenyl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“145”)

The title compound was prepared in an analogous manner as Example (142).LC-MS (M+1=464, obsd=464)

5-(4-fluoropheny)6-(4-((4-fluorophenyl)(2-(pyrrolidin-1-yl)ethoxy)methyl)-piperidin-1-yl)pyrimidin-4-amine(“146”)

To a solution of Example (138) (150 mg, 0.38 mmol, 1.0 eq) in DMF (10mL) was added sodium hydride (75.67 mg, 1.89 mmol, 5.0 eq). The mixturewas stirred for 10 minutes, then 1-(2-chloro-ethyl)pyrrolidinehydrochloride (77.22 mg, 0.45 mmol, 1.2 eq) was added. The mixture wasstirred at 70° C. overnight. After standard workup, the title compoundwas obtained through reverse phase HPLC purification. LC-MS (M+1=494,obsd=494)

5-(4-fluoropheny)6-(4-((4-fluorophenyl)(2-(dimethylamino)ethoxy)methyl)piperidin-1-yl)pyrimidin-4-amine (“147”)

The title compound was prepared in an analogous manner as Example (146).LC-MS (M+1=468, obsd=468)

5-(4-fluoropheny)-6-(4-((4-fluorophenyl)(pyrrolidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-amine(“148”)

Intermediate (148.1):6-{4-[Chloro-(4-fluoro-phenyl)-methyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine

To a solution of Example (140) (700 mg, 1.77 mmol, 1.0 eq) in DCM (10mL) was added thionyl chloride (0.32 mL, 4.41 mmol, 2.5 eq) dropwise.The mixture was stirred overnight. After removal of the solvents, thesolid was suspended in ethyl acetate and filtered to give Intermediate(94.1). LC-MS (M+1: 415, obsd: 415)

A mixture of Intermediate (148.1) (50 mg, 0.12 mmol, 1.0 eq),pyrrolidine (17.14 mg, 0.24 mmol, 2 eq) and DIEA (77.88 mg, 0.60 mmol, 5eq) in NMP (3 mL) was stirred at 120° C. overnight. The title compoundwas obtained through reverse phase HPLC purification. LC-MS (M+1=450,obsd=450)

5-(4-fluoropheny)-6-(4-((4-fluorophenyl)(3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-amine(“149”)

The title compound was prepared in an analogous manner as Example (148).LC-MS (M+1=486, obsd=486)

1-(6-amino-5-(4-fluoropheny)pyrimidin-4-yl)(4-((4-fluorophenyl))methyl)-dimethylethane-1,2-diamine(“150”)

The title compound was prepared in an analogous manner as Example (148).LC-MS (M+1=467, obsd=467)

5-(4-fluorophenyl)-(6-(4-fluoropheny)piperidin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-amine(“151”)

The title compound was prepared in an analogous manner as Example (148).LC-MS (M+1=493, obsd=493)

Examples (152) to (194) were prepared according to Synthetic Scheme 8.

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3-trifluoromethyl-phenyl)-acetonitrile(“152”)

In a round bottom flask equipped with a stir bar was dissolved5-(4-Fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (1 eq) and3-trifluoromethyl-benzaldehyde (1.05 eq) in acetonitrile. The vial wassealed with a rubber septa, then evacuated and backfilled with argon. Tothis sealed vessel was added trimethylsilyl cyanide (1.05 eq) and thereaction was allowed to stir at room temperature until complete. Thereaction is quenched by addition of an equal amount of ammonium chloride(saturated, aqueous solution), then extracted with ethyl acetate. Theorganic layers are then dried over sodium sulfate, filtered andconcentrated to give the title compound. LC-MS: (M+1=457, obsd.=457).

6-{4-[2-Amino-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“153”)

To a stirred mixture of Example (152) (76.0 mg; 0.17 mmol; 1.0 eq.) andCobalt chloride (2.2 mg; 0.02 mmol; 0.1 eq.) in Methanol (5.0 ml),sodium borohydride (32.8 mg; 0.83 mmol; 5.0 eq.) was added in portionsat 0° C. Reaction was left at RT after addition and stirred until deemedcomplete by LCMS. The mixture was purified through reverse phase HPLC toprovide the title compound. LC-MS: (M+1=461, obsd.=461).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-fluoro-3-trifluoromethyl-phenyl)-acetonitrile(“154”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=475, obsd.=475)

6-{4-[2-Amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“155”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=479, obsd.=479).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3,4-dichloro-phenyl)-acetonitrile(“156”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=457, obsd.=457)

6-{4-[2-Amino-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“157”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=461, obsd.=461).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-fluoro-phenyl)-acetonitrile(“158”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=407, obsd.=407)

6-{4-[2-Amino-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“159”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=411, obsd.=411).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3-chloro-4-fluoro-phenyl)-acetonitrile(“160”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=441, obsd.=441)

6-{4-[2-Amino-1-(3-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“161”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=445, obsd.=445).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-chloro-phenyl)-acetonitrile(“162”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=423, obsd.=423).

6-{4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“163”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=427, obsd.=427).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-chloro-3-fluoro-phenyl)-acetonitrile(“164”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=441, obsd.=441)

6-{4-[2-Amino-1-(4-chloro-3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“165”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=445, obsd.=445)

[4-(6-Amino-5-bromo-pyrimidin-4-yl)-piperazin-1-yl]-(3-trifluoromethyl-phenyl)-acetonitrile(“166”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=442, obsd.=442)

[4-(6-Amino-5-bromo-pyrimidin-4-yl)-piperazin-1-yl]-(4-trifluoromethyl-phenyl)-acetonitrile(“167”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=442, obsd.=442)

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-trifluoromethyl-phenyl)-acetonitrile(“168”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=442, obsd.=442)

6-{4-[2-Amino-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“169”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=411, obsd.=411)

6-{4-[2-Amino-1-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“170”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=479, obsd.=479)

6-[4-((1R,2R)-1-Aminomethyl-2-phenyl-propyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“171”)

The title compound was prepared in an analogous manner as Example (153)then isolated by the SFC chiral separation. LC-MS: (M+1=421, obsd.=421)

6-[4-((1R,2S)-1-Aminomethyl-2-phenyl-propyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“172”)

The title compound was prepared in an analogous manner as Example (153)then isolated by the SFC chiral separation. LC-MS: (M+1=421, obsd.=421)

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(6-chloro-pyridin-3-yl)-acetonitrile(“173”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=424, obsd.=424)

6-{4-[2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“174”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=428, obsd.=428)

6-{4-[(R)-2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“175”)

The title compound was isolated by the SFC chiral separation of Example(174). LC-MS: (M+1=428, obsd.=428)

6-{4-[(S)-2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“176”)

The title compound was isolated by the SFC chiral separation of Example(174). LC-MS: (M+1=428, obsd.=428)

6-{4-[2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“177”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=362, obsd.=362)

6-{4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“178”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=361, obsd.=361)

6-{4-[(S)-2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“179”)

The title compound was isolated by the SFC chiral separation of Example(178). LC-MS: (M+1=361, obsd.=361)

6-{4-[(R)-2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“180”)

The title compound was isolated by the SFC chiral separation of Example(178). LC-MS: (M+1=361, obsd.=361)

6-{4-[2-Amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“181”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=385, obsd.=385)

2-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)-2-(6-methoxypyridin-3-yl)acetonitrile(“182”)

The title compound was prepared in an analogous manner as Example (152).LC-MS (M+1=420, obsd.=420).

6-(4-(2-amino-1-(6-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“183”)

The title compound was prepared in an analogous manner as Example (153).LC-MS (M+1=424, obsd.=424).

2-(4-(6-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)-2-(4-(methylsulfonyl)phenyl)acetonitrile(“184”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=439, obsd.=439).

6-(4-(2-amino-1-(4-(methylsulfonyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“185”)

The title compound was prepared in an analogous manner as Example (153).LC-MS (M+1=443, obsd.=443).

6-(4-(2-amino-1-(4-(trifluoromethoxy)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“186”)

The title compound was prepared in an analogous manner as Example (153).LC-MS (M+1=449, obsd.=449).

6-(4-(2-amino-1-(4-chloro-3-fluorophenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“187”)

The title compound was prepared in an analogous manner as Example (153).LC-MS (M+1=417, obsd.=417).

6-[4-(2-Amino-1-cyclohexyl-ethyl)-piperazin-1-yl]-5-ethyl-pyrimidin-4-ylamine(“188”)

To a solution of[4-(6-Amino-5-ethyl-pyrimidin-4-yl)-piperazin-1-yl]-cyclohexyl-acetonitrile(28.00 mg; 0.09 mmol; 1.00 eq.) in THF (4.00 ml; 49.37 mmol; 579.16eq.), lithium 9-bbn hydride (0.38 ml; 0.38 mmol; 4.50 eq.) in THF wasadded, and the mixture stirred at 50° C. for four hours. LC-MS analysisindicated the reaction is incomplete, starting material still present.Add 0.1 ml more of lithium 9-bbn hydride solution and stir the reactionmixture overnight at 60° C. LC-MS analysis indicated the reaction wascomplete. The reaction mixture was filtered through a glass membranesyringe filter unit and evaporated to dryness. The residue was dissolvedin DMSO (3 ml) and purified by reverse phase HPLC (Waters, basic buffer)to afford the title compound (13.9 mg; 0.04 mmol) as a white glass in47.2% yield. LC-MS: (M+1=333.4, obsd.=333.3).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile(“189”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=458.4, obsd.=458.2).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-pyridin-3-yl-acetonitrile(“190”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=390.4, obsd.=390.2).

{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-cyclohexyl-acetonitrile(“191”)

The title compound was prepared in an analogous manner as Example (152).LC-MS: (M+1=395.5, obsd.=395.3).

6-{4-[2-Amino-1-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“192”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=479.4, obsd.=479.3).

6-[4-(2-Amino-1-pyridin-3-yl-ethyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“193”)

The title compound was prepared in an analogous manner as Example (153).LC-MS: (M+1=394.4, obsd.=394.2).

6-{4-[2-Amino-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“194”)

The title compound was obtained by the hydrogenation of{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile(20.00 mg; 0.04 mmol; 1.00 eq.) in 15 ml of Methanol and 50 mg of Pd/C10% stirring in a Parr shaker overnight at room temperature and purifiedby reverse phase low pressure chromatography (Yamazen, basic buffer).LC-MS: (M+1=462.4, obsd.=462.5).

Examples (195) to (208) were prepared according to Synthetic Scheme 9.

N-[3-Amino-1-(6-amino-5-bromo-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“195”)

A mixture of 5-bromo-6-chloropyrimidin-4-amine (272.7 mg; 1.24 mmol;1.02 eq.), N-[(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamidedihydrochloride (400.0 mg; 1.22 mmol; 1.0 eq.), potassium carbonate(336.8 mg; 2.44 mmol; 2.0 eq.) in DMSO (5.00 ml) was stirred at 60° C.overnight. The react ion mixture was workup and the crude was purifiedby reverse phase pre-HPLC (Waters, basic condition) to afford the titlecompound in 76% yield. LC-MS: (M+1=427, obsd.=427).

N-[3-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“196”)

A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (72.0 mg; 0.47mmol; 1.02 eq.),N-[(3-aminopyrrolidin-3-yl)methyl]-2,4-difluorobenzamide dihydrochloride(150.0 mg; 0.46 mmol; 1.0 eq.), potassium carbonate (126.3 mg; 0.91mmol; 2.0 eq.) in DMSO (2.00 ml) was stirred at 60° C. for 2 h. The reaction mixture was workup and the crude was purified by reverse phasepre-HPLC (Waters, acetonitrile/0.1% NH4OH in water) to afford the titlecompound in 70% yield. LC-MS: (M+1=374, obsd.=374).

4-Amino-6-{3-amino-3-[(2,4-difluoro-benzoylamino)-methyl]-pyrrolidin-1-yl}-pyrimidine-5-carboxamide(“197”)

Hydrogen peroxide (0.38 ml; 4.29 mmol; 40.0 eq.) was added dropwise tothe mixture ofN-{[3-amino-1-(6-amino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide(40.0 mg; 0.11 mmol; 1.0 eq.) and potassium carbonate (118.45 mg; 0.86mmol; 8.0 eq.) in DMSO (3.0 ml) at room temperature. The resultingmixture was then stirred at 40° C. for 2 hours. The reaction mixture wasworkup and the crude was purified by reverse phase chromatography(Yamazen, acetonitrile/0.1% NH4OH in water) to yield the title compoundin 40% yield. LC-MS: (M+1=392, obsd.=392).

N-{3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“198”)

A mixture ofN-{[3-amino-1-(6-amino-5-bromopyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide(70.0 mg; 0.16 mmol; 1.0 eq.), 4-fluorophenylboronic acid (45.8 mg; 0.33mmol; 2.0 eq.), palladium acetate (1.8 mg; 0.01 mmol; 0.05 eq.),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (6.7 mg; 0.02 mmol;0.10 eq.) and cesium carbonate (160.1 mg; 0.49 mmol; 3.0 eq.) in dioxane(4 ml) and water (0.5 ml) in the microwave vial was heated at 100° C.for 30 min. The reaction mixture was workup and the crude was purifiedby pre-HPLC (Waters, acetonitrile/0.1% NH4OH in water) to afford thetitle compound in 61% yield. LC-MS: (M+1=443, obsd.=443).

N-{3-Amino-1-[6-amino-5-(4-cyano-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“199”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=450, obsd.=450).

N-{3-Amino-1-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“200”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=517, obsd.=517).

N-{3-Amino-1-[6-amino-5-(6-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“201”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=456, obsd.=456).

N-{3-Amino-1-[6-amino-5-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“202”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=493, obsd.=493).

N-[3-Amino-1-(6-amino-5-phenyl-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“203”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=425, obsd.=425).

N-{3-Amino-1-[6-amino-5-(3-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“204”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=443, obsd.=443).

N-[3-Amino-1-(6-amino-5-pyridin-4-yl-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“205”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=426, obsd.=426).

N-{3-Amino-1-[6-amino-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“206”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=510, obsd.=510).

N-[4-Amino-1-(6-amino-5-bromo-pyrimidin-4-yl)-piperidin-4-ylmethyl]-2,4-difluoro-benzamide(“207”)

Intermediate 207.1:N-(4-Amino-piperidin-4-ylmethyl)-2,4-difluoro-benzamide dihydrochloride

To a solution of 4-Amino-4-aminomethyl-piperidine-1-carboxylic acidtert-butyl ester (250 mg; 1.1 mmol; 1.0 eq.) in pyridine (12 ml) at roomtemperature, a 0.1 M DCM solution of 2,4-difluoro-benzoyl chloride(182.8 mg; 1.04 mmol; 0.95 eq.) was added slowly. The reaction mixturewas quenched by adding 0.5 mL of methanol when LC-MS showing no startingmaterial remaining. The reaction mixture and concentrated to dryness toafford4-Amino-4-[(2,4-difluoro-benzoylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester.

A mixture of the crude4-amino-4-[(2,4-difluoro-benzoylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester (300 mg; 0.82 mmol; 1.0 eq.) and 4M hydrogenchloride in 1,4-dioxane (2.0 ml; 8.1 mmol; 10 eq.) in methanol (2 ml)was stirred at room temperature for 2 h. LC-MS showed the reaction isdone. Ether was added. The precipitate was filtered, washed with etherand dried to yield the Intermediate (207.1) as an off-white solid in 68%yield.

Example (207) was prepared in an analogous manner as Example (195) usingthe Intermediate (207.1) instead ofN-[(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamidedihydrochloride. LC-MS: (M+1=441, obsd.=441).

N-{4-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperidin-4-ylmethyl}-2,4-difluoro-benzamide(“208”)

The title compound was prepared in an analogous manner as Example (198).LC-MS: (M+1=457, obsd.=457).

Examples (214) to (247) were prepared according to Synthetic Scheme 10.

4-Amino-1-(6-amino-5-ethyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“214”)

Intermediate 214.1:(S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide

To 4-tert-Butoxycarbonylamino-piperidine-1,4-dicarboxylic acidmono-tert-butyl ester (1350.00 mg; 3.92 mmol; 1.00 eq.) in DMF (10 ml)was added HATU (1639.48 mg; 4.31 mmol; 1.10 eq.) and stirred at RT for40 mins. DIEA (1.48 ml; 8.23 mmol; 2.10 eq.) was added, followed by(S)-3-amino-3-(4-chloro-phenyl)-propan-1-ol (1013.56 mg; 3.92 mmol; 1.00eq.). The reaction mixture was stirred for another 3 h. The reactionsolution was poured into water (100 ml) and extracted with ethylacetate.The separated organic layer was washed with brine, dried andconcentrated. The residue was treated with ether to afford the a whitesolid, which was added 5 ml of methanol, 10 ml of 4.0 MHCl in dioxaneand stirred at RT overnight. The precipitate was filtered and was washedwith ether to yield Intermediate (214.1) as white solid.

The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (50.0 mg;0.32 mmol; 1.0 eq.), Intermediate (214.1) (140.3 mg; 0.33 mmol; 1.05eq.) and DIEA (131.54 mg; 0.95 mmol; 3.00 eq.) in DMSO (1.5 ml) wasstirred at 120° C. for 24 h. The crude was purified by HPLC to affordthe title compound (yield 31%). LC-MS (M+1=433, obsd.=433).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-propyl]-amide (“215”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=424, obsd.=424).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2,2,2-trifluoroethyl]-amide (“216”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=464, obsd.=464).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-2-carbamoyl-1-(4-chloro-phenyl)ethyl]-amide (“217”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=453, obsd.=453).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-ethyl]-amide (“218”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=400, obsd.=400).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-propyl]-amide (“219”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=414, obsd.=414).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2,2,2-trifluoroethyl]-amide (“220”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=454, obsd.=454).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-2-carbamoyl-1-(4-chloro-phenyl)-ethyl]-amide (“221”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=443, obsd.=443).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-ethyl]-amide (“222”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=410, obsd.=410).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propyl]-amide (“223”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=473, obsd.=473).

4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid [(S)-1-(4-chloro-phenyl)-ethyl]-amide (“224”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=441, obsd.=441).

4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid [(S)-1-(4-chloro-phenyl)-propyl]-amide (“225”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=455, obsd.=455).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-phenyl-propyl)-amide (“226”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=396, obsd.=396).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-p-tolyl-propyl)-amide (“227”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=410, obsd.=410).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-phenyl-propyl)-amide (“228”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=405, obsd.=405).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-methoxy-phenyl)-propyl]-amide (“229”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=426, obsd.=426).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propyl]-amide (“230”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=464, obsd.=464).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-pyridin-4-yl-propyl)-amide (“231”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=397, obsd.=397).

4-Amino-6-[4-amino-4-((S)-3-hydroxy-1-p-tolyl-propylcarbamoyl)-piperidin-1-yl]-pyrimidine-5-carboxylicacid amide (“232”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=428, obsd.=428).

4-Amino-6-{4-amino-4-[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“233”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=482, obsd.=482).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“234”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=440, obsd.=440).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“235”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=440, obsd.=440).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide (“236”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=423, obsd.=423).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-p-tolyl-propyl)-amide (“237”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=419, obsd.=419).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-methoxy-phenyl)-propyl]-amide (“238”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=435, obsd.=435).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-pyridin-4-yl-propyl)-amide (“239”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=406, obsd.=406).

4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid [(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“240”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=471, obsd.=471).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“241”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=430, obsd.=430).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“242”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=430, obsd.=430).

4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-fluoro-phenyl-3-hydroxy-propyl]-amide (“243”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=414, obsd.=414).

4-Amino-6-{4-amino-4-[(S)-1-(4-chloro-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“244”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=418, obsd.=418).

4-Amino-6-{4-amino-4-[(S)-1-(4-chloro-phenyl)-propylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“245”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=432, obsd.=432).

4-Amino-6-{4-amino-4-[(R)-1-(4-chloro-phenyl)-2-methoxy-ethylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“246”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=448, obsd.=448).

4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“247”)

The title compound was prepared in an analogous manner as Example (214).LC-MS: (M+1=448, obsd.=448).

N-{(R)-3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“248”)

The title compound was isolated by the SFC chiral separation of Example(198). LC-MS: (M+1=443, obsd.=443).

N-{(S)-3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“249”)

The title compound was isolated by the SFC chiral separation of Example(198). LC-MS: (M+1=443, obsd.=443).

Biological Activity

The IC₅₀ values reported for the compounds in the Experimental sectionwere derived from the following protocol for the p70S6K enzyme assay.

P70S6K Enzyme Assay

P70S6K inhibitor compounds were diluted and plated in 96 well plates. Areaction mixture including the following components was then added tothe compound plate to initiate the enzyme reaction; P70S6K (3 nM, T412Emutant, Millipore) was mixed with 24 μM ATP in an assay buffercontaining 100 mM Hepes (pH 7.5), 5 mM MgCl2, 1 mM DTT, 0.015% Brij and1 μM of the substrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from theS6 ribosomal protein sequence, FITC=fluorescein isothiocyanate,AHA=6-aminohexanoic acid). The reaction was incubated for 90 min at 25°C., before the addition of 10 mM EDTA to stop the reaction. Theproportion of substrate and product (phosphorylated) peptide wasanalysed on a Caliper Life Sciences Lab Chip 3000, using a pressure of−1.4 psi, and upstream and downstream voltages of −3000 and −700respectively. Product peaks were resolved before substrate peaks on theresulting chromatograms.

The values for the p70S6K enzyme inhibition assay for the compounds setout in the Experimental section are presented in Table 4.

TABLE 4 p70S6K Enzyme Inhibition by Compounds Described by Formula (I)Compound No. IC₅₀ p70S6K (nM) 1 5.8 2 2.2 3 2.6 4 4.5 5 330 6 6.3 7 2.88 3.4 9 5.7 10 31 11 280 12 18 13 7.2 14 38 15 4.9 16 4.9 17 1.7 18 1819 19 20 69 21 35 22 20 23 12 24 5.3 25 3.4 26 45 27 4.2 28 260 29 >100030 34.5 31 40 32 48.5 33 48.5 34 57 35 >1000 36 14 37 5.8 38 100 39 1240 11 41 14 42 6 43 98 44 150 45 210 46 630 47 960 48 66 49 16 50 450 5141 52 3.3 53 3.2 54 4.5 55 5.2 56 22 57 4.7 58 31 59 140 60 74 61 33 62980 63 980 64 50 65 120 66 82 67 24 68 >1000 69 >1000 70 >1000 71 >100072 >1000 73 >1000 74 370 75 15 76 >1000 77 640 78 >1000 79 >1000 80 7981 >1000 82 29 83 1000 84 15000 85 2800 86 6400 87 8700 88 6700 89 270090 600 91 6300 92 300 93 4300 94 1600 95 3500 96 140 97 3700 98 260 99670 100 900 101 3800 102 1400 103 920 104 920 105 640 106 320 107 5200108 3700 109 1900 110 450 111 190 112 460 113 >1000 114 3300 115 >100000116 290 117 24000 118 140 119 22000 120 1100 121 900 122 950 123 360 1243400 125 1200 126 390 127 550 128 280 129 610 130 >100000 131 1500 1321400 133 >100000 134 300 135 3600 136 — 137 3100 138 2.5 139 17 140 4.6141 1000 142 13 143 27 144 17 145 120 146 11 147 2 148 250 149 460 15033 151 200 152 >1000 153 11 154 >1000 155 14 156 130 157 6 158 240 1594.4 160 590 161 4 162 68 163 1.3 164 44 165 0.9 166 6100 167 >1000 168240 169 4.1 170 12 171 73 172 280 173 110 174 8.5 175 2.6 176 0.8 177200 178 69 179 13 180 190 181 180 182 220 183 3.4 184 >1000 185 60 1861.4 187 6.1 188 >1000 189 140 190 230 191 200 192 13.0 193 31.0 194 9.8195 3.3 196 50 197 530 198 4.8 199 11 200 120 201 9.5 202 9.1 203 5.3204 2.6 205 25 206 1000 207 150 208 46 209 — 210 — 211 — 212 — 213 — 214450 215 190 216 820 217 820 218 200 219 140 220 3200 221 140 222 620 22322000 224 87 225 78 226 820 227 280 228 2800 229 450 230 18000 231 3600232 23000 233 41000 234 560 235 250 236 900 237 860 238 380 239 7200 240100 241 210 242 98 243 390 244 20000 245 2400 246 5000 247 3600 248 290249 5.9

The invention claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt, solvate, or solvate of saltthereof, wherein: X is N or CH; Y is N; E is

R¹ is H, Hal is F, Cl, Br or I; each LA is independently an unbranchedor branched, linear saturated or partially unsaturated hydrocarbon chainhaving 1, 2, 3 4, 5 or 6 C atoms, wherein 1, 2 or 3 H atoms may bereplaced by Hal or OH; each Ar is independently a mono- or bicyclicaromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atomsand 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or,independently of one another, mono- or disubstituted by Hal, LA, OH, SH,O(LA), NH₂, NH(LA), N(LA)₂, NO₂, CN, OCN, COOH, COO(LA), CONH₂,CONH(LA), CON(LA)₂, NHCO(LA), NHCONH(LA), NHCONH₂, CHO and CO(LA),and/or monosubstituted by Cyc² or O-Cyc²; each Cyc¹ is independently a3, 4, 5 or 6 membered monocyclic aliphatic homo- or heterocycle having0-2 heteroatoms, selected from O, S and N, which may be mono- ordisubstituted by Hal, LA, NH₂, NH(LA), N(LA)₂, HO(LA)-; each Cyc² isindependently a 5 or 6 membered monocyclic aromatic homo- or heterocyclehaving 0-3 heteroatoms, selected from O, S and N, which may be mono- ordi-substituted by Hal or LA; and n is 1 or
 2. 2. The compound accordingto claim 1 wherein X is N, or a pharmaceutically acceptable salt,solvate, or solvate of salt thereof.
 3. The compound according to claim1, selected from:6-{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“71”);6-{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“73”);6-{4-[1-(3-fluorophenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“76”);6-{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“78”); and6-{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“79”); or a pharmaceutically acceptable salt, solvate, or solvate ofsalt thereof.
 4. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt, solvate, orsolvate of salt thereof, as active ingredient, together with apharmaceutically acceptable carrier.
 5. A method for treating cancer,comprising administering to a subject a compound of claim 1, or apharmaceutically acceptable salt, solvate, or solvate of salt thereof.6. W The method of claim 5, wherein said cancer is selected from thegroup consisting of brain, lung, colon, epidermoid, squamous cell,bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver,ovarian, prostate, colorectal, uterine, rectal, oesophageal, testicular,gynecological, thyroid cancer, melanoma, hematologic malignancies suchas acute myelogenous leukemia, multiple myeloma, chronic myelogneousleukemia, myeloid cell leukemia, glioma and Kaposi's sarcoma.
 7. A kitconsisting of separate packs of a) an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt, solvate, orsolvate of salt thereof, and b) an effective amount of a furthermedicament active ingredient.
 8. The compound according to claim 1,wherein Ar is phenyl or pyridyl, which is unsubstituted or mono- ordisubstituted by Hal, LA or O(LA), or a pharmaceutically acceptablesalt, solvate, or solvate of salt, thereof.
 9. The compound according toclaim 1, wherein X is N, Ar is phenyl or pyridyl, which is unsubstitutedor mono- or disubstituted by Hal, LA or O(LA), or a pharmaceuticallyacceptable salt, solvate, or solvate of salt thereof.
 10. A compoundselected from:6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine(“1”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“2”)6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“4”)6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-bromo-pyrimidin-4-ylamine(“5”)6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“6”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“7”)(R)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“9”),5-(4-fluorophenyl)-6-(4-(2-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)-phenyl)-ethyl)-piperazin-1-yl)-pyrimidin-4-amine(“10”)5-bromo-6-(4-(2-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“11”)5-(4-Fluoro-phenyl)-6-{4-[2-piperidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“12”)5-(4-Fluoro-phenyl)-6-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-pyrimidin-4-ylamine(“13”)5-bromo-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“14”)(S)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“16”)(R)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“17”)5-(6-aminopyridin-3-yl)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)-phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“20”)6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-vinylpyrimidin-4-amine(“21”)2-(4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)-piperazin-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol(“22”) Methyl4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)benzoate (“23”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclohex-1-en-1-yl)pyrimidin-4-amine(“24”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclopent-1-en-1-yl)pyrimidin-4-amine(“25”)4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)benzoicacid (“26”)5-Cyclopropyl-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine(“28”)5-Bromo-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“29”)5-(4-Fluoro-phenyl)-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“30”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-methoxypyrimidin-4-amine(“31”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine(“33”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(benzyloxy)pyrimidin-4-amine(“34”) (35)4-amino-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-ol (“35”)4-Amino-6-{4-[2-amino-l-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine-5-carbonitrile(“36”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrrol-3-yl)pyrimidin-4-amine(“37”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“38”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine(“39”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“40”)6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“41”)6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“42”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-ylamine(“43”)3-[2-{4-[6-Amino-5-(1-methyl-1H-pyrazol-3-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-(4-trifluoromethyl-phenyl)-ethylamino]-2,3-dimethyl-butan-2-ol(“44”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-((3-fluoroazetidin-1-yl)methyl)pyrimidin-4-amine(“45”) 5-Bromo-6{4-(4-chlorobenzyl)-piperidin-1-yl}pyrimidin-4-amine(“46”)5-Bromo-6{4-(4-trifluoromethylbenzyl)-piperidin-1-yl}pyrimidin-4-amine(“47”)5-(4-Fluorophenyl)-6{4-(4-trifluoromethylbenzyl)-piperidin-1-yl}pyrimidin-4-amine(“48”)5-(4-Fluorophenyl)-6{4-(4-chlorobenzyl)-piperidin-1-yl}pyrimidin-4-amine(“49”)5-(4-Fluorophenyl)-6{4-(4-(4-fluorophenyl)benzyl)-piperidin-1-yl}pyrimidin-4-amine(“50”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine(“51”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“52”)6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“54”)(S)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“56”)(R)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“57”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine(“58”)6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperidin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine(“59”)2-((4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)methyl)-4,5-dichlorophenol(“60”)2-(1-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)ethyl)-5-chlorophenol(“61”)6-(4-(2-(azetidin-3-yloxy)-4,5-dichlorobenzyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“62”)6-(4-{1-[2-(Azetidin-3-yloxy)-4-chloro-phenyl]-ethyl}-piperazin-1-yl)-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“63”)5-(4-Fluorophenyl)-6{4-[1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“64”)5-(4-Fluorophenyl)-6{4-[1-(3-trifluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“65”)5-(4-Fluorophenyl)-6{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“66”)5-(4-Fluorophenyl)-6{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“67”)5-Bromo-6{4-[1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“68”)5-Bromo-6{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“69”)5-Bromo-6{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“70”)6-{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“71”)5-Bromo-6{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“72”)6-{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“73”)6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-fluoro-pyrimidin-4-ylamine(“74”)5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“75”)6-{4-[1-(3-fluorophenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“76”)5-Bromo-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“77”)6-{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“78”)6-{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“79”)5-Chloro-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“81”)(R)5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“82”)(S)-5-(4-Fluorophenyl)-6{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine(“83”)6-{4-[2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“84”)4-(1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“85”)4-(1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“86”)6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“87”)4-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“88”)4-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“89”)6-{4-[2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“90”)3-((R)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“91”)6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“92”)6-{4-[(R)-2-Azetidin-1-yl-1-(4-methanesulfonyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“93”)6-{4-[(R)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“94”)6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“95”)4-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“96”)3-((S)-1-{4-[6-Amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“97”)6-{4-[(S)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“98”)6-{4-[2-Azetidin-1-yl-1-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“99”)6-{4-[2-Azetidin-1-yl-1-(2,3-difluoro-4-methyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“100”)6-{4-[2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“101”)6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“102”)6-{4-[(R)-2-Azetidin-1-yl-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“103”)6-{4-[(R)-2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“104”)6-{4-[(S)-2-Azetidin-1-yl-1-(3-fluoro-4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“105”)4-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“106”)6-{4-[(R)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“107”)6-{4-[(S)-2-Azetidin-1-yl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“108”)6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-methyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“109”)4-((S)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“110”)4-((R)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzoicacid methyl ester (“111”)6-{4-[4-Azetidin-1-yl-1-(4-chloro-phenyl)-butyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“113”)6-{4-[2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethoxy-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“114”)6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“115”)6-{4-[2-Azetidin-1-yl-1-(4-imidazol-1-yl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“116”)[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid ethyl ester (“117”)6-(1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-3H-benzothiazol-2-one(“118”)[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid ethyl ester (“119”)6-{4-[2-Azetidin-1-yl-1-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“120”)6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“121”)6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“122”)6-{4-[2-Azetidin-1-yl-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“123”)6-{4-[2-Azetidin-1-yl-1-(2,3-difluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“124”)3-((S)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“125”)6-{4-[2-Azetidin-1-yl-1-(2,3-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“126”)6-{4-[2-Azetidin-1-yl-1-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“127”)6-{4-[2-Azetidin-1-yl-1-(4-methanesulfonyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“128”)3-((R)-1-{4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-2-azetidin-1-yl-ethyl)-benzonitrile(“129”)[4-(4-Amino-6-{4-[2-azetidin-1-yl-1-(3-cyano-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-5-yl)-pyrazol-1-yl]-aceticacid methyl ester (“130”)6-{4-[2-Azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“131”)6-{4-[2-Azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“132”)6-{4-[2-Azetidin-1-yl-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-ylamine(“133”)6-{4-[2-Azetidin-1-yl-1-(2-chloro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“134”)6-{4-[2-Azetidin-1-yl-1-(3-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“135”)6-{4-[2-Azetidin-1-yl-1-(2-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine(“137”)1-6-amino-5-(4-fluoropheny)pyrimidin-4-yl)piperidin-4-yl-4-(chlorophenyl)methanol(“138”)1-6-amino-5-(4-fluoropheny)pyrimidin-4-yl)piperidin-4-yl-4-(4-fluorophenyl)phenyl)methanol(“139”)1-6-amino-5-(4-fluoropheny)pyrimidin-4-yl)piperidin-4-yl-4-(fluorophenyl)methanol(“140”)1-6-amino-5-(vinylpyrimidin-4-yl)piperidin-4-yl-4-(fluorophenyl)methanol(“141”)5-(4-Fluorophenyl)-6{4-amino(4-chlorophenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“142”)5-(4-Fluorophenyl)-6{4-amino(4-fluorophenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“143”)5-(4-Fluorophenyl)-6{4-amino(4-(4-fluorophenyl)phenyl)methyl-piperidin-1-yl}pyrimidin-4-amine(“144”)6-(4-((cyclopentylamino)(4-fluorophenyl)methyl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine(“145”)5-(4-fluoropheny)6-(4-((4-fluorophenyl)(2-(pyrrolidin-1-yl)ethoxy)methyl)-piperidin-1-yl)pyrimidin-4-amine(“146”) 5-(4-fluoropheny)6-(4-((4-fluorophenyl)(2-(dimethlyamino)ethoxy)methyl)piperidin-1-yl)pyrimidin-4-amine (“147”)5-(4-fluoropheny)-6-(4-((4-fluorophenyl)(pyrrolidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-amine(“148”)5-(4-fluoropheny)-6-(4-((4-fluorophenyl)(3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-amine(“149”)1-(6-amino-5-(4-fluoropheny)pyrimidin-4-yl)(4-((4-fluorophenyl))methyl)-dimethylethane-1,2-diamine(“150”) 5-(4-fluorophenyl)-(6-(4-fluoropheny)piperidin-4-ylmethyl)amino)methyl)piperidin-1-yl)pyrimidin-4-amine (“151”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3-trifluoromethyl-phenyl)-acetonitrile(“152”)6-{4-[2-Amino-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“153”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-fluoro-3-trifluoromethyl-phenyl)-acetonitrile(“154”)6-{4-[2-Amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“155”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3,4-dichloro-phenyl)-acetonitrile(“156”)6-{4-[2-Amino-1-(3,4-dichloro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“157”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-fluoro-phenyl)-acetonitrile(“158”)6-{4-[2-Amino-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“159”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(3-chloro-4-fluoro-phenyl)-acetonitrile(“160”)6-{4-[2-Amino-1-(3-chloro-4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“161”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-chloro-phenyl)-acetonitrile(“162”)6-{4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“163”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-chloro-3-fluoro-phenyl)-acetonitrile(“164”)[4-(6-Amino-5-bromo-pyrimidin-4-yl)-piperazin-1-yl]-(3-trifluoromethyl-phenyl)-acetonitrile(“166”)[4-(6-Amino-5-bromo-pyrimidin-4-yl)-piperazin-1-yl]-(4-trifluoromethyl-phenyl)-acetonitrile(“167”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(4-trifluoromethyl-phenyl)-acetonitrile(“168”)6-{4-[2-Amino-1-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“170”)6-[4-((1R,2R)-1-Aminomethyl-2-phenyl-propyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“171”)6-[4-((1R,2S)-1-Aminomethyl-2-phenyl-propyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“172”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-(6-chloro-pyridin-3-yl)-acetonitrile(“173”)6-{4-[2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“174”)6-{4-[(S)-2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“176”)6-{4-[2-Amino-1-(6-chloro-pyridin-3-yl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“177”)6-{4-[2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“178”)6-{4-[(R)-2-Amino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“180”)6-{4-[2-Amino-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-piperazin-1-yl}-5-ethyl-pyrimidin-4-ylamine(“181”)2-(4-(6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)piperazin-1-yl)-2-(6-methoxypyridin-3-yl)acetonitrile(“182”) 6-(4-(2-amino-1-(6-methoxypyridin-3-yl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine (“183”)2-(4-(6-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl)piperazin-1-yl)-2-(4-(methylsulfonyl)phenyl)acetonitrile(“184”)6-(4-(2-amino-1-(4-(methylsulfonyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“185”)6-(4-(2-amino-1-(4-chloro-3-fluorophenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine(“187”)6-[4-(2-Amino-1-cyclohexyl-ethyl)-piperazin-1-yl]-5-ethyl-pyrimidin-4-ylamine(“188”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-pyridin-3-yl-acetonitrile(“190”){4-[6-Amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-cyclohexyl-acetonitrile(“191”)6-{4-[2-Amino-1-(2-fluoro-5-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“192”)6-[4-(2-Amino-1-pyridin-3-yl-ethyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine(“193”)N-[3-Amino-1-(6-amino-5-bromo-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“195”)N-[3-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“196”)4-Amino-6-{3-amino-3-[(2,4-difluoro-benzoylamino)-methyl]-pyrrolidin-1-yl}-pyrimidine-5-carboxamide(“197”)N-{3-Amino-1-[6-amino-5-(4-cyano-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“199”)N-{3-Amino-1-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“200”)N-{3-Amino-1-[6-amino-5-(6-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“201”)N-{3-Amino-1-[6-amino-5-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“202”)N-[3-Amino-1-(6-amino-5-phenyl-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“203”)N-{3-Amino-1-[6-amino-5-(3-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“204”)N-[3-Amino-1-(6-amino-5-pyridin-4-yl-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl]-2,4-difluoro-benzamide(“205”)N-{3-Amino-1-[6-amino-5-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“206”)N-[4-Amino-1-(6-amino-5-bromo-pyrimidin-4-yl)-piperidin-4-ylmethyl]-2,4-difluoro-benzamide(“207”)N-{4-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperidin-4-ylmethyl}-2,4-difluoro-benzamide(“208”)4-Amino-1-(6-amino-5-ethyl-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“214”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-propyl]-amide (“215”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2,2,2-trifluoroethyl]-amide (“216”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-2-carbamoyl-1-(4-chloro-phenyl)ethyl]-amide (“217”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-ethyl]-amide (“218”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-propyl]-amide (“219”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2,2,2-trifluoroethyl]-amide (“220”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-2-carbamoyl-1-(4-chloro-phenyl)-ethyl]-amide (“221”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-ethyl]-amide (“222”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propyl]-amide (“223”)4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid [(S)-1-(4-chloro-phenyl)-ethyl]-amide (“224”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-phenyl-propyl)-amide (“226”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-p-tolyl-propyl)-amide (“227”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-phenyl-propyl)-amide (“228”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-methoxy-phenyl)-propyl]-amide (“229”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propyl]-amide (“230”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-pyridin-4-yl-propyl)-amide (“231”)4-Amino-6-[4-amino-4-((S)-3-hydroxy-1-p-tolyl-propylcarbamoyl)-piperidin-1-yl]-pyrimidine-5-carboxylicacid amide (“232”)4-Amino-6-{4-amino-4-[(S)-3-hydroxy-1-(4-trifluoromethyl-phenyl)-propylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“233”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“234”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“235”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide (“236”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-p-tolyl-propyl)-amide (“237”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-3-hydroxy-1-(4-methoxy-phenyl)-propyl]-amide (“238”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid((S)-3-hydroxy-1-pyridin-4-yl-propyl)-amide (“239”)4-Amino-1-[6-amino-5-(1H-pyrazol-4-yl)-pyrimidin-4-yl]-piperidine-4-carboxylicacid [(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“240”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“241”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-chloro-phenyl)-3-hydroxy-propyl]-amide (“242”)4-Amino-1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(S)-1-(4-fluoro-phenyl)-3-hydroxy-propyl]-amide (“243”)4-Amino-6-{4-amino-4-[(S)-1-(4-chloro-phenyl)-ethylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“244”)4-Amino-6-{4-amino-4-[(S)-1-(4-chloro-phenyl)-propylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“245”)4-Amino-6-{4-amino-4-[(R)-1-(4-chloro-phenyl)-2-methoxy-ethylcarbamoyl]-piperidin-1-yl}-pyrimidine-5-carboxylicacid amide (“246”)4-Amino-1-(6-amino-5-chloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid[(R)-1-(4-chloro-phenyl)-2-methoxy-ethyl]-amide (“247”)N-{(R)-3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“248”) andN-{(S)-3-Amino-1-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-pyrrolidin-3-ylmethyl}-2,4-difluoro-benzamide(“249”).